Oxymorphone, generally administered in the form of its hydrochloride salt, is a potent semi-synthetic opiate analgesic. Oxymorphone hydrochloride is indicated for the relief of moderate to severe pain and has been approved for use in the United States since 1959. Oxymorphone hydrochloride is also indicated as a pre-operative medication to alleviate apprehension, maintain anesthesia and as an obstetric analgesic. Additionally, oxymorphone hydrochloride may be used to alleviate pain in patients with dyspnea associated with acute left ventricular failure and pulmonary edema. It can be administered as an injectable solution, suppository, tablet or extended release tablet.
Some crystalline forms of oxymorphone hydrochloride are known. For example, U.S. Pat. No. 8,563,571 describes 10 crystalline forms of oxymorphone hydrochloride, including a commercially produced form of oxymorphone hydrochloride Form A, a sesquihydrate (also referred to herein as oxymorphone hydrochloride Form I). U.S. Pat. No. 7,851,482 describes a hydrated form of oxymorphone hydrochloride having less than 10 ppm of 14-hydroxymorphinone. Other crystalline forms of oxymorphone hydrochloride, including mixtures of forms, are described in, for example, U.S. Pat. No. 7,851,482, U.S. Pat. No. 8,563,571 and WO 2012/163796.
Oxymorphone hydrochloride can be produced by processes that utilize oripavine, a compound derived from opium poppy. Generally, these processes involve oxidizing oripavine to form 14-hydroxymorphinone, an α,β-unsaturated ketone (ABUK), and then converting 14-hydroxymorphinone to oxymorphone base by catalytic hydrogenation. If desired, oxymorphone base can be converted to its hydrochloride salt by suspending or dissolving the base in a solvent or solvent/water mixture (e.g. ethanol and water) and adding hydrochloric acid to the mixture, as described for example in WO2008/048711.
The conversion of 14-hydroxymorphinone to oxymorphone base usually results in some amount of 14-hydroxymorphinone present in the isolated oxymorphone base. Thus, the final oxymorphone hydrochloride salt typically also contains 14-hydroxymorphinone. This is problematic as ABUKs, including 14-hydroxymorphinone, are suspected genotoxic impurities. Accordingly, several processes have been developed to reduce the amount of 14-hydroxymorphinone in oxymorphone hydrochloride salt. For example, US 2012/0059167 describes processes for reducing the concentration of ABUK impurities in morphinan-6-one products by treatment with a sulfur-containing compound. U.S. Pat. No. 7,851,482 describes a method of preparing oxymorphone hydrochloride product containing less than 10 ppm of 14-hydroxymorphinone, which includes hydrogenating oxymorphone hydrochloride in a strongly acidic solvent/water mixture. However, the process described in the '482 patent can result in an oxymorphone hydrochloride product that contains some residual solvent and thus the product must be further dried and then hydrated in a separate step, as described in U.S. Pat. No. 7,851,482, Example 3.2D. The present invention overcomes this additional processing to directly obtain crystalline oxymorphone hydrochloride Form I.